Opioid formulations

ABSTRACT

A depot precursor formulation comprising:
         a) a controlled-release matrix;   b) at least oxygen containing organic solvent;   c) at least 12% by weigh of at least one active agent selected from buprenorphine and salts thereof, calculated as buprenorphine free base.       

     Corresponding depot compositions and methods of treatment in pain management, by opioid maintenance and related methods are provided.

The present application is a continuation application of U.S. patentapplication Ser. No. 15/866,043, filed Jan. 9, 2018, which is adivisional application of U.S. patent application Ser. No. 14/416,421,filed Jan. 22, 2015 (now U.S. Pat. No. 9,937,164), which is a 371national phase entry of PCT Application No. PCT/EP13/65855, filed Jul.26, 2013, which claims priority to U.S. Provisional Application No.61/806,185, filed Mar. 28, 2013, and to U.S. patent application Ser. No.13/558,463, filed Jul. 26, 2012, each of which is hereby incorporated byreference in its entirety.

The present invention relates to formulation precursors(pre-formulations) for the in situ generation of controlled releaseopioid compositions. In particular, the invention relates to sustainedrelease compositions and corresponding precursor formulations,containing at least one opioid bioactive agent, especiallybuprenorphine.

Many bioactive agents including pharmaceuticals, nutrients, vitamins andso forth have a “functional window”. That is to say that there is arange of concentrations over which these agents can be observed toprovide some biological effect. Where the concentration in theappropriate part of the body (e.g. locally or as demonstrated by serumconcentration) falls below a certain level, no beneficial effect can beattributed to the agent. Similarly, there is generally an upperconcentration level above which no further benefit is derived byincreasing the concentration. In some cases increasing the concentrationabove a particular level, results in undesirable or even dangerouseffects.

Some bioactive agents have a long biological half-life and/or a widefunctional window and thus may be administered occasionally, maintaininga functional biological concentration over a substantial period of time(e.g. 6 hours to several days). In other cases the rate of clearance ishigh and/or the functional window is narrow and thus to maintain abiological concentration within this window regular (or even continuous)doses of a small amount are required. This can be particularly difficultwhere non-oral routes of administration (e.g. parenteral administration)are desirable or necessary. Furthermore, in some circumstances, such asin the fitting of implants (e.g. joint replacements or oral implants)the area of desired action may not remain accessible for repeatedadministration. Similarly, patient compliance may limit how regularlyand/or how frequently administration can be made. In such cases a singleadministration must provide active agent at a therapeutic level over andextended period, and in some cases over the whole period during whichactivity is needed.

In the case of opioid active agents, the situation can be complex.Opioids administered for pain relief are given only to the extent neededbecause of the risk of dependence but effective pain management oftenrequires at least a background level of stable administration.Furthermore, the administrative burden in supplying opioids isrelatively high because of the danger of diversion for illicit use. Thefacility to provide a long-acting opioid administration for use insituations where pain relief for several days will inevitably benecessary (e.g. post operative pain relief, relief of cancer pain and/orrelief of chronic pain such as chromic back pain) could thereforeimprove the experience for the patient and reduce the burden on thehealthcare professionals.

The situation of administering opioids to people with any form of opioiddependence is even more complex. Opioids will often be prescribed toavoid or relieve the symptoms of withdrawal in those with an opioiddependence, but such subjects may have a lifestyle that makes dailydosing by a healthcare professional difficult. Patient compliance maytherefore be a problem with such a regime. Some pharmaceuticals can besupplied to the patient for self-administration but the risk ofdiversion to illicit use is such that opioids are not typically suppliedin this way. The dose required to provide a functional plasmaconcentration is relatively high in daily products and this makes therisk of diversion much higher.

Various methods have been used and proposed for the sustained release ofbiologically active agents. Such methods include slow-release, orallyadministered compositions, such as coated tablets, formulations designedfor gradual absorption, such as transdermal patches, and slow-releaseimplants such as “sticks” implanted under the skin.

One method by which the gradual release of a bioactive agent has beenproposed is a so-called “depot” injection. In this method, a bioactiveagent is formulated with carriers providing a gradual release of activeagent over a period of a number of hours or days. These are often basedupon a degrading matrix which gradually disperses in the body to releasethe active agent.

A controlled-release product, especially in ready-made-up form, which isadministrable by simple injection offers a number of potentialadvantages, particularly in the treatment and management of opioiddependence. Such a product could be administered under the control of ahealthcare worker to minimise risk of diversion but requires only aminimum imposition on that worker's time since the administration isinfrequent (e.g. once a month). Ready-to-use products further do notrequire lengthy preparation.

The most common of the established methods of depot injection reliesupon a polymeric depot system. This is typically a biodegradable polymersuch poly (lactic acid) (PLA) and/or poly (lactic-co-glycolic acid)(PLGA) and may be in the form of a solution in an organic solvent, apre-polymer mixed with an initiator, encapsulated polymer particles orpolymer microspheres. The polymer or polymer particles entrap the activeagent and are gradually degraded releasing the agent by slow diffusionand/or as the matrix is absorbed. Examples of such systems include thosedescribed in U.S. Pat. Nos. 4,938,763, 5,480,656 and 6,113,943 and canresult in delivery of active agents over a period of up to severalmonths.

One alternative to the more established, polymer based, depot systemswas proposed in U.S. Pat. No. 5,807,573. This proposes a lipid basedsystem of a diacylglycerol, a phospolipid and optionally water,glycerol, ethylene glycol or propylene glycol to provide anadministration system in the reversed micellar “L₂” phase or a cubicliquid crystalline phase. Since this depot system is formed fromphysiologically well tolerated diacyl glycerols and phospholipids, anddoes not produce the lactic acid or glycolic acid degradation productsof the polymeric systems, there is less tendency for this system toproduce inflammation at the injection site. The liquid crystallinephases are, however, of high viscosity and the L₂ phase may also be tooviscous for ease of application. The authors of U.S. Pat. No. 5,807,573also do not provide any in vivo assessment of the release profile of theformulation and thus it is uncertain whether or not a “burst” profile isprovided.

The use of non-lamellar phase structures (such as liquid crystallinephases) in the delivery of bioactive agents is now relatively wellestablished. Such structures form when an amphiphilic compound isexposed to a solvent because the amphiphile has both polar and apolargroups which cluster to form polar and apolar regions. These regions caneffectively solubilise both polar and apolar compounds. In addition,many of the structures formed by amphiphiles in polar and/or apolarsolvents have a very considerable area of polar/apolar boundary at whichother amphiphilic compounds can be adsorbed and stabilised. Amphiphilescan also be formulated to protect active agents, to at least someextent, from aggressive biological environments, including enzymes, andthereby provide advantageous control over active agent stability andrelease.

The formation of non-lamellar regions in the amphiphile/water,amphiphile/oil and amphiphile/oil/water phase diagrams is a well knownphenomenon. Such phases include liquid crystalline phases such as thecubic P, cubic D, cubic G and hexagonal phases, which are fluid at themolecular level but show significant long-range order, and the L₃ phasewhich comprises a multiply interconnected bi-continuous network ofbilayer sheets which are non-lamellar but lack the long-range order ofthe liquid crystalline phases. Depending upon their curvature of theamphiphile sheets, these phases may be described as normal (meancurvature towards the apolar region) or reversed (mean curvature towardsthe polar region).

The non-lamellar liquid crystalline and L₃ phases are thermodynamicallystable systems. That is to say, they are not simply a meta-stable statethat will separate and/or reform into layers, lamellar phases or thelike, but are the stable thermodynamic form of the lipid/solventmixture.

While the effectiveness of known lipid depot formulations is high, thereare certain aspects in which the performance of these is less thanideal. One respect in which depot formulations could often be improvedis in injection volume. Since the administration is only occasional, theabsolute amount of active agent that must be administered iscomparatively high, but the controlled-release vehicle (e.g. polymer orlipid depot formulation) must also be contained within the injectionvolume. Lower injection volume provides faster and more comfortableadministration and improves patient compliance. However, doses aretypically limited by the level to which the active agent can beincorporated into the depot precursor mixture. It would therefore be aconsiderable advantage to provide a precursor formulation in whichgreater levels of opioid active such as buprenorphine can be containedwhile maintaining controlled-release properties.

As indicated above, a class of active agents having particular utilityas depot or slow-release formulations are opioids. The term “Opioids” asused herein encompasses a class of naturally occurring, semi-synthetic,and fully synthetic compounds which show agonistic and/or antagonisticproperties for at least one opioid receptor. Opioids are of very greatmedical value, being highly effective analgesics. They are typicallyused for pain relief after serious injuries and/or medical proceduresand for this use it can be of value to provide sustained dosing with alevel or gently tapering concentration of active agent to correspondwith a healing and recovery profile over a number of days or weeks.

Unfortunately, tolerance to, and physiological dependence upon, opioidscan develop, and can lead to behavioural addiction, especially wherefast-acting opioids are used and/or the drugs are abused. Furthermore,abuse of opioids is common because of the euphoric effects which can becaused by their sudden administration. Withdrawal from opioids wheredependence has developed can be unpleasant, especially from fast-actingopioids which are commonly abused, such as diacetylmorphine (heroin) orfentanyl. One approach for assisting recovering addicts is thus totransfer them from fast-acting opioids to slower-acting drugs which canbe taken less frequently without causing the symptoms of withdrawal.Patients may then be provided with a maintenance level of theslower-acting opioid or gradually weaned from this by a gentlydecreasing dose regime.

Typical candidates for use as this slower-acting “opioid-replacement”drug are methadone and buprenorphine, and studies have shown that thesecan significantly reduce the chances of relapse in recovering addicts.One of the advantages of these opioids over the abused substances isthat they generally do not require administration so frequently in orderto avoid withdrawal symptoms. Methadone, for example, needs to beadministered daily, while the 37-hour half-life of buprenorphine meansthat a single dose is effective for 1-2 days, or longer in somepatients. Weekly patches of buprenorphine are also available, althoughat present these are for use in pain management rather than in curbingaddiction and have limited bioavailability. Excess drug is thereforeused and waste patches are liable for misuse and misdirection.

The two primary dosing methods for these slow-acting opioids inaddiction therapy are “detox”, in which a tapering dose is provided overa period of around 2 weeks, and “maintenance”, in which a level dose isprovided over a longer term of, typically, a few months. In both cases,and with any of the known opioid preparations, frequent administrationis generally required, which in turn requires on-going patientcompliance. Evidently, it would be a considerable advantage to provideslow-release formulations which could be administered infrequently, andwould provide a level, or gradually tapering, drug profile, to allowgradual detox or longer term maintenance without requiring frequentadministration.

Previous lipid depot formulations of buprenorphine (e.g. U.S. Pat. No.8,236,755) are highly effective, but provide a maximum of only around 9%buprenorphine concentration by weight. Polymeric systems, such asWO2001/154724, have been formulated with up to 20% buprenorphine butthere remains scope for precursor formulations with enhanced dragloading levels.

The present inventors have now established that by appropriate choice ofcomponents, a pre-formulation comprising certain opioid active agents,particularly buprenorphine, can be formulated with a greaterconcentration of active agent than demonstrated hitherto whilemaintaining the controlled-release effect of the preparation. Certain ofthese precursor formulations (pre-formulations) are easy to manufacture,may be sterile-filtered, have low viscosity (allowing easy and lesspainful administration), allow a high bioavailability of active agent(thus allowing a smaller total amount of opioid to be used) and/orprovide for effective dose control by means of control of active agentconcentration and/or injection volume.

In a first aspect, the present invention thus a depot precursorformulation comprising:

a) a controlled-release matrix;

b) at least oxygen containing organic solvent;

c) at least 12% by weigh of at least one active agent selected frombuprenorphine and salts thereof, calculated as buprenorphine free base.

Such a depot precursor will typically form a depot composition in situupon administration to the body of a subject. In the case offormulations comprising a lipid controlled-release matrix, this willtypically be by uptake of aqueous fluid to form a structured (e.g.liquid crystal) phase. In the case of a polymer-based controlled-releasematrix component the depot will generally be formed by loss of solvent.

Suitable controlled-release matrices thus include lipid controlledrelease formulations (as described herein) and polymeric release matrixsystems (as described herein).

The high-loading depot precursor formulations of the present invention(as well as the other corresponding aspects) will typically comprisegreater than 15% (e.g. 15 to 50%) by weight of active agent, preferablyat least 21% and more preferably at least 25% by weight. Greater than30% by weight is particularly preferred. Active agents will generally bebuprenorphine or salts thereof as indicated herein.

In a second aspect, the present invention also provides a depotcomposition formed or formable from any of the depot precursorformulations described herein. Such a depot composition may comprise:

-   a) a controlled-release matrix;-   b) optionally at least one oxygen containing organic solvent;-   c) at least 12% of at least one active agent selected from    buprenorphine and salts thereof-   d) optionally at least one aqueous fluid.

Such a depot composition will typically be formed upon exposure of aprecursor formulation of the present invention (such as any precursorformulation in any embodiment or preferred embodiment described herein)to an aqueous fluid in vivo. Exposure to such an aqueous fluid willgenerally result in a loss of solvent and/or an addition of water to theprecursor formulation and may result in a phase change such as fromsolution to solid (a precipitation) or from a low-viscosity phase, suchas a solution or L₂ phase to a high viscosity phase such as a liquidcrystalline phase.

In a further aspect of the invention, there is also provided a method ofsustained delivery of buprenorphine to a human or non-human animal body,said method comprising administering a depot precursor formulationcomprising:

-   a) a controlled-release matrix;-   b) at least oxygen containing organic solvent;-   c) at least 12% of at least one active agent selected from    buprenorphine and salts thereof.

Preferably, the precursor formulation (pre-formulation) administered insuch a method is a pre-formulation of the invention as described herein.

The method of administration suitable for the above method of theinvention will be a method appropriate for the condition to be treatedor addressed. A parenteral depot will thus be formed by parenteral (e.g.subcutaneous or intramuscular) administration. A bioadhesivenon-parenteral (e.g. topical) depot composition may be formed byadministration to the surface of skin, mucous membranes and/or nails, toophthalmological, nasal, oral or internal surfaces or to cavities suchas nasal, rectal, vaginal or buccal cavities, the periodontal pocket orcavities formed following extraction of a natural or implanted structureor prior to insertion of an implant (e.g a joint, stent, cosmeticimplant, tooth, tooth filling or other implant).

Since the key medicinal properties of opioids are analgesia and use indetoxification and/or maintenance from opioid dependence, theformulations will typically be for systemic absorption, although topicalpain relief can be provided by opioids and they are additionally ofvalue in cough suppression (especially codeine and hydrocodone),diarrhoea suppression, anxiety due to shortness of breath (especiallyoxymorphone) and antidepression (especially buprenorphine). For these,appropriate administration methods, such as bioadhesive pain-relievinggels for topical pain, or non-absorbed oral compositions for diarrhoeasuppression may be used.

In a further aspect, the present invention also provides a method forthe formation of a depot composition comprising exposing a precursorformulation comprising:

a) a controlled-release matrix;

b) at least oxygen containing organic solvent;

c) at least 12% by weight of at least one active agent selected frombuprenorphine and salts thereof.

to an aqueous fluid in vivo.

Suitable aqueous fluids are particularly body fluids as indicatedherein. Preferably the pre-formulation administered is a pre-formulationof the present invention as described herein and more preferably apreferred formulation according to the present invention. The exposureto a fluid “in vivo” may evidently be internally within the body or abody cavity, or may be at a body surface such as a skin surface,depending upon the nature of the composition.

In a still further aspect the present invention provides a process forthe formation of a precursor formulation suitable for the administrationof an opioid bioactive agent to a (preferably mammalian) subject, saidprocess comprising forming a mixture of

a) a controlled-release matrix; and

b) at least one oxygen containing organic solvent;

and dissolving or dispersing at least 12% by weight of at least onebuprenorphine in the mixture, or in at least one of components a, or bprior to forming the low viscosity mixture. Preferably thepre-formulation so-formed is a formulation of the invention as describedherein. The process may additionally comprise sterilisation, such as bysterile filtration.

In a still further aspect, the present invention additionally providesfor a method of treatment or prophylaxis of a human or non-human animalsubject comprising administration of a precursor formulation asdescribed herein. Such a method may be for the treatment of pain or forthe treatment of drug dependence (typically opioid dependence) bydetoxification and/or maintenance as described herein.

As used herein, the term “low viscosity mixture” is used to indicate amixture which may be readily administered to a subject and in particularreadily administered by means of a standard syringe and needlearrangement. This may be indicated, for example by the ability to bedispensed from a 1 ml disposable syringe through a 23 gauge (22AWG/0.635 mm diameter) needle by manual pressure. In a further preferredembodiment, the low viscosity mixture should be a mixture capable ofpassing through a standard sterile filtration membrane such as a 0.22 μmsyringe filter. In other preferred embodiments, a similar functionaldefinition of a suitable viscosity can be defined as the viscosity of apre-formulation that can be sprayed using a compression pump orpressurized spray device using conventional spray equipment. A typicalrange of suitable viscosities would be, for example, 0.1 to 5000 mPas,preferably 1 to 1000 mPas at 20° C. (e.g. 10 to 1000 mPas or 50 to 1000mPas at 20° C.).

It has been observed that by the addition of small amounts of lowviscosity solvent, as indicated herein, a very significant change inviscosity can be provided, particularly for lipid formulations (asdescribed herein). As indicated in Example 11 below, for example, theaddition of only 5% solvent (in the case of Example 11, ethanol) canreduce viscosity of a lipid mixture by several orders of magnitude.Addition of 10% solvent will cause a still greater effect. In order toachieve this non-linear, synergistic effect, in lowering viscosity it isimportant that a solvent of appropriately low viscosity and suitablepolarity be employed. Such solvents include those described hereininfra.

Particularly preferred examples of low viscosity mixtures are molecularsolutions (of both polymer depot precursor formulations and lipidprecursor formulations), suspensions of microbeads (of polymer matrices)and/or isotropic phases such as L₂ and/or L₃ phases (of lipid precursorformulations). As describe above, the L₃ is a non-lamellar phase ofinterconnected sheets which has some phase structure but lacks thelong-range order of a liquid crystalline phase. Unlike liquidcrystalline phases, which are generally highly viscous, L₃ phases are oflower viscosity. Obviously, mixtures of L₃ phase and molecular solutionand/or particles of L₃ phase suspended in a bulk molecular solution ofone or more components are also suitable. The L₂ phase is the so-called“reversed micellar” phase or microemulsion. Most preferred low viscositymixtures are molecular solutions, L₃ phases and mixtures thereof. L₂phases are less preferred, except in the case of swollen L₂ phases asdescribed herein.

The present invention provides a pre-formulation comprising componentsa, b and at least 12% of at least one opioid bioactive agent asindicated herein. In one particularly preferred embodiment, thecontrolled release matrix component a) comprises a lipid controlledrelease formulation. Such a formulation will preferably comprise:

i) at least one neutral diacyl and/or triacyl lipid and/or a tocopherol;and

ii) at least one phospholipid;

A preferably embodiment of this will be:

i) at least one neutral diacyl lipid and/or a tocopherol; and

ii) at least one phospholipid;

One of the considerable advantages of the lipid precursor formulationsof the invention is that components i) and ii) may be formulated in awide range of proportions. In particular, it is possible to prepare anduse pre-formulations of the present invention having a much greaterproportion of phospholipid to neutral, diacyl lipid and/or tocopherolthan was previously achievable without risking phase separation and/orunacceptably high viscosities in the pre-formulation. The weight ratiosof components i):ii) may thus be anything from 5:95 right up to 95:5.Preferred ratios would generally be from 90:10 to 20:80 and morepreferably from 85:15 to 30:70. A highly suitable range is i):ii) in theratio 40:60 to 80:20, especially around 50:50, e.g. 45:55 to 60:40. Inone preferred embodiment of the invention, there is a greater proportionof component ii) than component i). That is, the weight ratio i):ii) isbelow 50:50, e.g. 48:52 to 2:98, preferably, 40:60 to 10:90 and morepreferably 35:65 to 20:80. In an alternative and highly valuableembodiment, there may be an equal or greater amount of component i) incomparison with component ii). In such an embodiment, there may be, forexample, a weight ratio of 50:50 to 80:20 of components i) to ii). Aratio of 50:50 to 70:30 may also be suitable.

Corresponding to the above, the amount of component i) in the precursorformulations may be, for example, 10% to 90% (e.g. 18 to 90%) by weightof the total formulation, preferably 10% to 70%, such as 12% to 40% or12% to 30% by weight of the total formulation. In one embodiment, theabsolute amount of component i) by weight is no less than the amount ofcomponent ii).

Similarly, the amount of component ii) in the precursor formulations maybe, for example, 8% to 90% (e.g. 18 to 90%) by weight of the totalformulation, preferably 8% to 70%, such as 10% to 40% or 10% to 30% byweight of the total formulation.

The total amount of component a) in the formulation will typically be 20to 70%, such as 30 to 60 wt % based upon the weight of the totalformulation.

In an alternative embodiment of the invention, component a) may compriseat least one polymer release matrix. Such matrices are typicallybiodegradable polymers. Such polymers are well known in the art and maybe homopolymers, mixtures of homopolymers, copolymers, mixtures ofcopolymers and/or mixtures of homopolymers and copolymers. Polyestersand/or polyamides are particularly suitable, of which biodegradablepolyesters are preferred. Examples of suitable polyesters includepolylactate, polyglycolate, polylactate-co-glycolate(polylactate/glycolate copolymer) and mixtures thereof.Polylactate-co-glycolate (PLGA) is particularly suitable.

Polymers may be in the form of a solution or may be used as microspheres(microbeads) in suspension. PLGA microspheres are one preferredembodiment.

The amount of component b in the pre-formulations of the invention willbe at least sufficient to provide a low viscosity mixture (e.g. amolecular solution, see above) of components a, b and the buprenorphineactive, and will be easily determined for any particular combination ofcomponents by standard methods. The phase behaviour of lipidformulations may be analysed by techniques such as visual observation incombination with polarized light microscopy, nuclear magnetic resonance,x-ray or neutron diffraction, and cryo-transmission electron microscopy(cryo-TEM) to look for solutions, L₂ or L₃ phases, or liquid crystallinephases. Viscosity may be measured directly by standard means. Asdescribed above, an appropriate practical viscosity is that which caneffectively be syringed and particularly sterile filtered. This will beassessed easily as indicated herein.

A key feature of the present invention is the facility to incorporate ahigher level of buprenorphine active agent (e.g, buprenorphine or a saltthereof) than has been observed previously. The present inventors haveobserved that the capability of a low-viscosity mixture to containbuprenorphine active agent is greatly enhanced by the inclusion of atleast one amide solvent in component b). Correspondingly, component b)preferably comprises at least one amide. As a comparison, for example, alipid formulation prepared with ethanol as component b) can typicallydissolve up to 9% of buprenorphine active agent. When an amide solventsuch as NMP is utilised, this can increase to 35% or greater whilemaintaining a valuable release profile. Particularly preferred amidecompounds which may be comprised in component b) includeN-Methyl-2-pyrrolidone (NMP) dimethyl formamide (DMF) and dimethylacetamide (DMA). NMP is most preferred.

The weight of solvent component b incorporated into the precursorformulation will depend crucially upon the type of sustained releaseformulation a) that is in use. For example, a polymeric sustainedrelease formulation in solution might require the solvent to be presentat 40 to 70% by weight in order to ensure a sufficiently low viscosityand full solubilisation. In contrast, the solvent level typically usedfor a lipid-based controlled release formulation would generally bearound 0.5 to 50% of the total weight of the precursor formulation. Forthe high loading compositions of the present invention, this proportionis preferably (especially for injectable depots) 20 to 40% and morepreferably 20 to 38% or 25 to 35% by weight. A highly suitable range isaround 30%, e.g. 15 to 45%, especially, 10 to 30% or 10 to 40% by weightof the complete composition. Thus, overall, a solvent level of 1 to 50%of the total precursor formulation weight is appropriate and suitableranges for each embodiment will be clear to those with experience in theart. In one embodiment, a precursor formulation and corresponding depot& method are provided in which the administration period is one doseeach month and the solvent content is 30%±10%.

Component “i)” as indicated herein is a neutral lipid componentcomprising a polar “head” group and also non-polar “tail” groups.Generally the head and tail portions of the lipid will be joined by anester moiety but this attachment may be by means of an ether, an amide,a carbon-carbon bond or other attachment. Preferred polar head groupsare non-ionic and include polyols such as glycerol, diglycerol and sugarmoieties (such as inositol and glucosyl based moieties); and esters ofpolyols, such as acetate or succinate esters. Preferred polar groups areglycerol and diglycerol, especially glycerol.

Diacyl glycerols of component i) will comprise glycerol and two acylchains as indicated herein. Correspondingly, triacyl glycerols arepreferred triacyl lipids and they will comprise a glycerol “head” groupand three independently chosen acyl chains as indicated herein.Preferred aspects as indicated herein will apply correspondingly.

In one preferred aspect, component i) is a diacyl lipid in that it hastwo non-polar “tail” groups. This is generally preferable to the use ofmono-acyl (“lyso”) lipids because these are typically less welltolerated in vivo. The two non-polar groups may have the same or adiffering number of carbon atoms and may each independently be saturatedor unsaturated. Examples of non-polar groups include C₆-C₃₂ alkyl andalkenyl groups, which are typically present as the esters of long chaincarboxylic acids. These are often described by reference to the numberof carbon atoms and the number of unsaturations in the carbon chain.Thus, CX:Z indicates a hydrocarbon chain having X carbon atoms and Zunsaturations. Examples particularly include caproyl (C6:0), capryloyl(C8:0), capryl (C10:0), lauroyl (C12:0), myristoyl (C14:0), palmitoyl(C16:0), phytanoly (C16:0), palmitoleoyl (C16:1), stearoyl (C18:0),oleoyl (C18:1), elaidoyl (C18:1), linoleoyl (C18:2), linolenoyl (C18:3),arachidonoyl (C20:4), behenoyl (C22:0) and lignoceroyl (C24:9) groups.Thus, typical non-polar chains are based on the fatty acids of naturalester lipids, including caproic, caprylic, capric, lauric, myristic,palmitic, phytanic, palmitolic, stearic, oleic, elaidic, linoleic,linolenic, arachidonic, behenic or lignoceric acids, or thecorresponding alcohols. Preferable non-polar chains are palmitic,stearic, oleic and linoleic acids, particularly oleic acid. In onepreferred embodiment, component i) comprises components with C16 to C18alkyl groups, particularly such groups having zero, one or twounsaturations. In particular, component i) may comprise at least 50% ofcomponents having such alkyl groups.

The diacyl lipid, when used as all or part of component “i)”, may besynthetic or may be derived from a purified and/or chemically modifiednatural sources such as vegetable oils. Mixtures of any number of diacyllipids may be used as component i). Most preferably this component willinclude at least a portion of diacyl glycerol (DAG), especially glyceroldioleate (GDO). In one favoured embodiment, component i) consists ofDAGs. These may be a single DAG or a mixture of DAGs. A highly preferredexample is DAG comprising at least 50%, preferably at least 80% and evencomprising substantially 100% GDO.

An alternative or additional highly preferred class of compounds for useas all or part of component i) are tocopherols. As used herein, the term“a tocopherol” is used to indicate the non-ionic lipid tocopherol, oftenknown as vitamin E, and/or any suitable salts and/or analogues thereof.Suitable analogues will be those providing the phase-behaviour, lack oftoxicity, and phase change upon exposure to aqueous fluids, whichcharacterise the compositions of the present invention. Such analogueswill generally not form liquid crystalline phase structures as a purecompound in water. The most preferred of the tocopherols is tocopherolitself, having the structure below. Evidently, particularly where thisis purified from a natural source, there may be a small proportion ofnon-tocopherol “contaminant” but this will not be sufficient to alterthe advantageous phase-behaviour or lack of toxicity. Typically, atocopherol will contain no more than 10% of non-tocopherol-analoguecompounds, preferably no more than 5% and most preferably no more than2% by weight.

In one embodiment of the invention, component i) consists essentially oftocopherols, in particular tocopherol as shown above.

A preferred combination of constituents for component i) is a mixture ofat least one DAG (e.g. at least one C16 to C18 DAG, such as GDO) with atleast one tocopherol. Such mixtures include 2:98 to 98:2 by weighttocopherol:GDO, e.g. 10:90 to 90:10 tocopherol:GDO and especially 20:80to 80:20 of these compounds. Similar mixtures of tocopherol with otherDAGs are also suitable.

Component “ii)” in lipid embodiments of the present invention is atleast one phospholipid. As with component i), this component comprises apolar head group and at least one non-polar tail group. The differencebetween components i) and ii) lies principally in the polar group. Thenon-polar portions may thus suitably be derived from the fatty acids orcorresponding alcohols considered above for component i). In particularC16 to C18 acyl groups having zero, one or two unsaturations are highlysuitable as moieties forming the non-polar group of the compounds ofcomponent ii). It will typically be the case that the phospholipid willcontain two non-polar groups, although one or more constituents of thiscomponent may have one non-polar moiety. Where more than one non-polargroup is present these may be the same or different.

Preferred phospholipid polar “head” groups include phosphatidylcholine(PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) andphosphatidylinositol (PI). PC and PE are preferred lipids, bothindividually and as a mixture. In one embodiment, component b) maycomprise at least 70% PC, PE or mixtures thereof. Most preferred isphosphatidylcholine (PC). In a preferred embodiment, component ii) thuscomprises at least 50% PC, preferably at least 70% PC and mostpreferably at least 80% PC. Component ii) may consist essentially of PC.

The phospholipid portion, even more suitably than any diacyl lipidportion, may be derived from a natural source. Suitable sources ofphospholipids include egg, heart (e.g. bovine), brain, liver (e.g.bovine) and plant sources including soybean. Such sources may provideone or more constituents of component ii), which may comprise anymixture of phospholipids.

Since the pre-formulations of the invention are to be administered to asubject for the controlled release of an active agent, it is preferablethat the components i) and ii), as well as any alternative controlledrelease matrix are biocompatible. In this regard, it is preferable touse, for example, diacyl lipids and phospholipids rather than mono-acyl(lyso) compounds. A notable exception to this is tocopherol, asdescribed above. Although having only one alkyl chain, this is not a“lyso” lipid in the convention sense. The nature of tocopherol as a welltolerated essential vitamin evidently makes it highly suitable inbiocompatibility.

It is furthermore most preferable that the lipids and phospholipids ofcomponents i) and ii) are naturally occurring (whether they are derivedfrom a natural source or are of synthetic origin). Naturally occurringlipids tend to cause lesser amounts of inflammation and reaction fromthe body of the subject. Not only is this more comfortable for thesubject but it may increase the residence time of the resulting depotcomposition, especially for parenteral depots, since less immune systemactivity is recruited to the administration site. In certain cases itmay, however, be desirable to include a portion of anon-naturally-occurring lipid in components i) and/or ii). This mightbe, for example an “ether lipid” in which the head and tail groups arejoined by an ether bond rather than an ester. Suchnon-naturally-occurring lipids may be used, for example, to alter therate of degradation of the resulting depot-composition by having agreater or lesser solubility or vulnerability to breakdown mechanismspresent at the site of active agent release. Although all proportionsfall within the scope of the present invention, generally, at least 50%of each of components i) and ii) will be naturally occurring lipids.This will preferably be at least 75% and may be up to substantially100%.

Two particularly preferred combinations of components i) and ii) are GDOwith PC and tocopherol with PC, especially in the region 10-30 wt %GDO/tocopherol, 5-25 wt % PC and 20-40% solvent (especially comprisingNMP). A composition of 15-25% GDO, 10-25% PC, with 20-35%, preferably25-32% solvent (e.g. NMP and optionally at least one of ethanol, benzylalcohol, propylene glycol, benzyl benzoate, dimethylsulphoxide etc) and12-45% (e.g. 31 to 40%), preferably 15-40% of at least one opioid activeagent is particularly effective. A ratio of PC/GDO: ˜0.25-1.5,preferably 0.6-1.2 is desirable in many cases (including otherembodiments indicated herein).

In addition to amphiphilic components i) and ii), lipid-basedpre-formulations of the invention may also contain additionalamphiphilic components at relatively low levels. In one embodiment ofthe invention, the pre-formulation contains up to 10% (by weight ofcomponents i) and ii)) of a charged amphiphile, particularly an anionicamphiphile such as a fatty acid. Preferred fatty acids for this purposeinclude caproic, caprylic, capric, lauric, myristic, palmitic, phytanic,palmitolic, stearic, oleic, elaidic, linoleic, linolenic, arachidonic,behenic or lignoceric acids, or the corresponding alcohols. Preferablefatty acids are palmitic, stearic, oleic and linoleic acids,particularly oleic acid. The formulations of the invention comprisingdiacyl lipids may also contain up to 10% of an optional triacylglycerol, such as those described herein.

Component “b” of the pre-formulations of the invention is an oxygencontaining organic solvent. Since the pre-formulation is to generate adepot composition following administration (e.g. in vivo), upon contactwith an aqueous fluid, it is desirable that this solvent be tolerable tothe subject and be capable of mixing with the aqueous fluid, and/ordiffusing or dissolving out of the pre-formulation into the aqueousfluid. Solvents having at least moderate water solubility are thuspreferred.

Typical solvents suitable for use as component b) include at least onesolvent selected from alcohols, ketones, esters (including lactones),ethers, amides (including lactams) and sulphoxides. Examples of suitablealcohols include ethanol, isopropanol, benzylalcohol and glycerolformal. Monools are preferred to diols and polyols. Where diols orpolyols are used, this is preferably in combination with an at leastequal amount of monool or other preferred solvent. Examples of ketonesinclude acetone and propylene carbonate. Suitable ethers includediethylether, glycofurol, diethylene glycol monoethyl ether,dimethylisobarbide, and polyethylene glycols. Suitable esters includeethyl acetate, benzyl benzoate and isopropyl acetate and dimethylsulphide is as suitable sulphide solvent. Suitable amides andsulphoxides include dimethylacetamide (DMA), n-methyl pyrrolidone (NMP),2-pyrrolidone and dimethylsulphoxide (DMSO). Less preferred solventsinclude dimethyl isosorbide, tetrahydrofurfuryl alcohol, diglyme andethyl lactate. The high loading nature of the precursor formulations isbelieved to be enabled or enhanced by the presence of at least one amidesolvent. NMP is a highly preferred solvent for use in combination withbuprenorphine. In one embodiment, component b) therefore comprises NMPand may comprise at least 50% or at least 70% NMP. Component b) mayconsist essentially of (e.g. >95%) or consist of NMP. NMP and ethanol isa further preferred combination and component b) may comprise or consistof a mixture of NMP and ethanol.

Since the pre-formulations are to be administered to a living subject,it is necessary that the solvent component b) is sufficientlybiocompatible. The degree of this biocompatibility will depend upon theapplication method and the volume injected. Furthermore, since componentb) may be any mixture of solvents, a certain amount of a solvent thatwould not be acceptable in large quantities may evidently be present.Overall, however, the solvent or mixture forming component b) must notprovoke unacceptable reactions from the subject upon administration.Generally such solvents will be hydrocarbons or preferably oxygencontaining hydrocarbons, both optionally with other substituents such asnitrogen containing groups. It is preferable that little or none ofcomponent b) contains halogen substituted hydrocarbons since these tendto have lower biocompatibility. Where a portion of halogenated solventsuch as dichloromethane or chloroform is necessary, this proportion willgenerally be minimised. Where the depot composition is to be formednon-parenterally a greater range of solvents may evidently be used thanwhere the depot is to be parenteral.

Component b) as used herein may be a single solvent or a mixture ofsuitable solvents but will generally be of low viscosity. This isimportant because one of the key aspects of the present invention isthat it provides preformulations that are of low viscosity and oneprimary role of a suitable solvent is to reduce this viscosity. Thisreduction will be a combination of the effect of the lower viscosity ofthe solvent and the effect of the molecular interactions between solventand controlled release formulation, such as the polymer or lipidcomposition. One observation of the present inventors is that theoxygen-containing solvents of low viscosity described herein have highlyadvantageous and unexpected molecular interactions with the lipid partsof the composition, thereby providing a non-linear reduction inviscosity with the addition of a small volume of solvent.

The viscosity of the “low viscosity” solvent component b) (singlesolvent or mixture) should typically be no more than 18 mPas at 20° C.This is preferably no more than 15 mPas, more preferably no more than 10mPas and most preferably no more than 7 mPas at 20° C.

The solvent component b) will generally be at least partially lost uponin vivo formation of the depot composition, or diluted by absorption ofwater from the surrounding air and/or tissue. It is preferable,therefore, that component b) be at least to some extent water miscibleand/or dispersible and at least should not repel water to the extentthat water absorption is prevented. In this respect also, oxygencontaining solvents with relatively small numbers of carbon atoms (forexample up to 10 carbons, preferably up to 8 carbons) are preferred.Obviously, where more oxygens are present a solvent will tend to remainsoluble in water with a larger number of carbon atoms. The carbon toheteroatom (e.g. N, O, preferably oxygen) ratio will thus often bearound 1:1 to 6:1, preferably 2:1 to 4:1. Where a solvent with a ratiooutside one of these preferred ranges is used then this will preferablybe no more than 75%, preferably no more than 50%, in combination with apreferred solvent (such as ethanol). This may be used, for example todecrease the rate of evaporation of the solvent from the pre-formulationin order to control the rate of liquid crystalline depot formation.

The pre-formulations of the present invention typically do not containsignificant amounts of water. Since it is essentially impossible toremove every trace of water from a lipid composition, this is to betaken as indicating that only such minimal trace of water exists ascannot readily be removed. Such an amount will generally be less than 1%by weight, preferably less than 0.5% by the weight of thepre-formulation. In one preferred aspect, the pre-formulations of theinvention do not contain glycerol, ethylene glycol or propylene glycoland contain no more than a trace of water, as just described.

There is, however, a certain embodiment of the present invention inwhich higher proportions of water may be tolerated. This is where wateris present as a part of the solvent component in combination with anadditional water-miscible component b (single solvent or mixture). Inthis embodiment, up to 15 wt % water may be present providing that atleast 3 wt %, preferably at least 5% and more preferably at least 7 wt %component b is also present, that component b is water miscible, andthat the resulting preformulation remains non-viscous and thus does notform a liquid crystalline phase. Generally there will be a greateramount of component b) by weight than the weight of water included inthe preformulation. Most suitable solvents of use with water in thisaspect of the invention include ethanol, isopropyl alcohol and NMP.

A key aspect of the present invention is that high loadings of BUP maybe used to reduce the injection volume necessary for a particular doseof buprenorphine (BUP). In one embodiment, the compositions of thepresent invention thus contain at least 140 mg/mL (e.g. 140 to 500mg/mL) of buprenorphine, preferably at least 200 mg/mL and morepreferably at least 300 mg/mL. A loading level of at least 340 mg/mL ispossible and advantageous in reducing injection volumes.

The pre-formulations of the present invention contain one or morebuprenorphine bioactive agents (described equivalently as “bioactiveagents”, “opioid active agents” or simply “active agents” herein).Active agents may be any suitably biotolerable form of any buprenorphinecompound having an effect (e.g. agonism and/or antagonism) at one ormore opioid receptors. Buprenorphine free base is the most preferredbuprenorphine active agent and where weight percentages are specifiedherein, these are in terms of the equivalent amount of buprenorphinefree base unless otherwise specified. Suitable salts, including mixturesthereof, may be used and these salts may be any biocompatible salt.Suitable salts include acetate, citrate, pamoate or halide (e.g.chloride or bromide) salts, or any of the many biocompatible salts whichare known in the art.

Buprenorphine is an opioid with mixed agonist-antagonist properties(also known as a partial agonist) that has been used in the treatment ofopioid dependence in a number of countries. It is approved by the Foodand Drug Administration (FDA) for the treatment of opioid dependence inthe United States and clinical studies have shown buprenorphine to beeffective in reducing opioid-positive urines and retaining patients inoutpatient maintenance treatment of opioid dependence, as well as in thedetoxification of opioid abusers.

Buprenorphine has a unique pharmacological profile with severalpotential strengths over other opioid treatments:

1. A ceiling on its agonist activity that may reduce its abuse liabilityand contribute to a superior safety profile.

2. Attenuation of physiological and subjective effects which likelycontributes to the suppression of opioid self-administration.

3. Slow receptor dissociation providing extended duration.

Importantly, buprenorphine treatment is associated with a relativelylow-intensity withdrawal syndrome upon discontinuation, making itparticularly promising for detoxification treatments.

Buprenorphine is currently available in sublingual dosing forms, whichrequire dosing every 1-2 days either at a clinic, or with “take-home”medication. Because of the potential for abuse of opioids, however,“take-home” of any opioid poses potential logistic and legislativeproblems. This is made more problematic by the low bioavailability ofexisting sublingual formulations meaning that the dose being “takenhome” is potentially quite a significant one.

A depot formulation of the present invention offers several advantagesin use for treating opioid dependence, including fast onset andrelatively stable levels of buprenorphine over time, thereby suppressingwithdrawal symptoms and blocking the effects of exogenously-administeredopioids for several weeks. The slow decay and elimination of the depotbuprenorphine could also provide a gradual opioid detoxification withminimal withdrawal syndrome. Hence, a buprenorphine depot may offer apromising approach for delivering effective opioid maintenance ordetoxification treatment. Furthermore, a depot formulation shouldminimize the burdens of patient compliance as it would require a lessfrequent dosing regimen, thereby also reducing the frequency of clinicvisits and the amount of clinical support needed. Finally, depotbuprenorphine should reduce the risks of misuse and drug diversion ofthe medication by eliminating or reducing the need for take-homemedication.

In one embodiment of the present invention, the bioavailability ofbuprenorphine as measured from time zero to time of last measurement andextrapolated to infinity for a single dose, or between two consecutivedoses at steady state, as the area under the curve of human plasmaconcentration against time is no less than 3 hours*ng/mL per mg,preferably no less than 5 hours*ng/ml per mg of administeredbuprenorphine, preferably no less than 7 and more preferably no lessthan 10 h ng/ml per mg of administered buprenorphine. This compares withless than 3 hour ng/ml per mg administered by current sublingualformulations.

Current sublingual formulations include Subutex® and Suboxone®. Both aresublingual tablets approved by the FDA for the treatment of opioidaddiction. Subutex contains only buprenorphine hydrochloride as activeagent. This formulation was developed as the initial product. The secondmedication, Suboxone also contains naloxone to guard against misuse.Subutex is typically given during the first few days of treatment, whileSuboxone is used during the maintenance phase of treatment. Both ofthese products contain a relatively large dose of buprenorphine becauseof their relatively low bioavailability. Thus, there is a risk ofdiversion of these products, especially since they are often prescribedfor self-administration. These FDA approved products are: Subutex(bitter sublingual, no active additives; in 2 mg and 8 mg dosages) andSuboxone (Lemon-lime flavored sublingual, one part naloxone for everyfour parts buprenorphine; hexagon shaped tablet in 2 mg and 8 mgdosages). The existing Suboxone product is also available in aclinically interchangeable “sublingual film” formulation. This filmproduct remains a once-daily dosage product and although it produces asomewhat higher Cmax than the sublingual tablet, the plasma profile andbioavailability are very similar to the tablet. The film product is thusavailable in the same 8 mg and 2 mg dosages as the sublingual tabletproduct.

The precursor formulations and all corresponding aspects of the presentinvention may be formulated with buprenorphine as the sole active agent.However, in one embodiment, the various formulations of the inventionmay be prepared as combination medicaments (e.g. with other opioidagonists and/or antagonists). For example, naloxone may be formulatedwith buprenorphine (e.g. at between 1:1 and 10:1 buprenorphine:naloxoneby wt). Other opioids may similarly be formulated with the buprenorphineactive agent of the present invention. This will apply particularly toprecursor formulations intended for pain control such as by analgesia.

A further key aspect of the present invention is the comparatively lowCmax (peak plasma concentration) in comparison with the doseadministered and the period over which the drug is effective. It can beseen, for example, in FIGS. 4a and 4b that administration of 16 mg ofbuprenorphine as Subutex gives a Cmax concentration of 6 ng/mL but iscleared to around 0.5 ng/mL in less than 24 hours. In comparison, a 15mg dose administered as a formulation of the present invention peakswith a Cmax of around 3.5 and remains at around 0.9 ng·mL at 7-daysfollowing administration.

Thus in a further preferred aspect, the compositions of the presentinvention provide a Cmax (maximum concentration) in human blood plasmaafter a single administration of no more than 0.3 ng/ml per mg ofadministered buprenorphine. This will preferably be no more than 0.22ng/mL per mg of buprenorphine administered and more preferably no morethan 0.17 ng/mL per mg administered. It can be seen in comparison thatSubutex gives a peak concentration of at least around 0.4 ng/mL per mgof buprenorphine administered.

A still further advantage of the compositions of the present inventionis the linearity of the AUC dose experienced by the subject incomparison with the administered dose of buprenorphine. This may be seenfrom FIG. 6 and allows the physician to control the experienced dosedirectly by control of the administered dose in a linear relationship.It can furthermore be seen that Cmax is additionally observed to varylinearly with administered dose and again this allows the medicalprofessional to control of the concentration experienced by the subject(FIG. 5). This linear or substantially linear relationship of AUC toinjected dose is also termed “dose proportionality”.

The compositions of the invention provide for an extended duration ofbuprenorphine release, e.g., as exemplified in FIG. 4a . Thus, thehalf-life plasma concentration experienced by the subject after Cmax maybe greater than 1 day, preferably greater than 2 days and mostpreferably greater than 3 days.

Because of the relatively low Cmax and the long half-life of thebuprenorphine depot-precursor formulations of the present invention, thevariation of plasma concentration during a cycle of administration (oncea steady-state has been achieved) will be less pronounced (and obviouslyless sudden) than is experienced by a subject taking a dailyadministration product. For example, the steady-state variation betweenCmax (the highest plasma concentration during a cycle of administration)and Cmin (the lowest plasma concentration over an administration cycleat steady-state (also termed Ctrough)) may be no more than 20-fold. Thusthe steady-state Cmax concentration may be no more than 20 times theCmin plasma concentration, preferably no more than 15 times and morepreferably no more than 10 times. Most preferably the Cmax/Cmin ratiowill be no more than 6.

Thus, the variation between Cmin and Cmax at a steady-state ofadministration of the products of the present invention may fall withthe range of between 0.4 ng/mL and 10 ng/mL, preferably falling withinthe range of 0.5 ng/mL and to 8 ng/mL. Such a range is highly suitablefor treatment of opioid dependence or for opioid maintenance therapy.

Because of the very high bioavailability of the buprenorphine formulatedin the preformulations of the present invention, the transition of asubject currently receiving daily sublingual buprenorphine to receiving,for example, monthly or weekly formulations according to the presentinvention will not generally require that the dose be increasedsignificantly. For example a subject may transfer from daily sublingualbuprenorphine to a weekly formulation of the present invention andreceive 0.5 to 3 times his previous daily dose administered weekly.Preferably the weekly dose will be 0.5 to 2 times the previous dailymaintenance dose.

The amount of bioactive agent to be formulated with the pre-formulationsof the present invention will depend upon the functional dose and theperiod during which the depot composition formed upon administration isto provide sustained release. Typically, the dose formulated for aparticular agent will be less than half of the equivalent of the normaldaily dose multiplied by the number of days the formulation is toprovide release. Preferably this will be less than one third and morepreferably less than one quarter of the total of the daily dosesadministered to that subject. Thus, for example, a subject receiving adaily sublingual dose of 8 mg buprenorphine might typically receivearound 22.5 mg every seven days as formulated according to the presentinvention.

The present inventors have observed that the blood plasma buprenorphineconcentration at which a subject requires a “rescue” dose ofbuprenorphine correlates directly to the maintenance dose that thesubject was receiving prior to transfer to a depot composition. This isshown graphically in FIG. 10. It can be seen from that figure that the“minimum effective” plasma level for opioid maintenance therapy variedfrom around 0.2 ng/mL to around 1 ng/mL as the previous mean maintenancedose for the different dose groups varied from 7 to 17 mg/day.Correspondingly, a lower dose of around 20-30 mg/month buprenorphineformulated according to the present invention might be appropriate forthose on a daily dose of up to 7 mg/day, while 50 to 100 mg/month mightbe appropriate for those transitioning from a daily dose of up to 17mg/day.

Since different subjects will have differing tolerance for opioids, itis important that a suitable dose can be selected by a medicalprofessional which will provide peak and plateau concentrations whichare acceptable to that subject.

Doses suitable for a once-weekly administration would typically be inthe range 3 to 40 mg buprenorphine (calculated as buprenorphine freebase), preferably 5 to 30 mg per week.

Doses suitable for a once-fortnightly administration would typically bein the range 6 to 60 mg buprenorphine (calculated as free base),preferably 10 to 50 mg per two weeks (i.e. per administration).

Doses suitable for once-monthly administration would typically be in therange 10 to 200 mg buprenorphine (calculated as free base), preferably10 to 180 mg per month (i.e. per administration). For a opioidsubstitution (maintenance) dose, 40-140 mg per month would be preferred.For a pain relieving dose, 10 to 50 mg per month would be appropriate.

For opioid dependence and poioid maintenance therapy, a dose providing ablood plasma concentration of at least 0.2 ng/mL (e.g. at least 0.4 orat least 0.8 or at least 1.0 ng/mL) is preferred.

Evidently this amount will need to be tailored to take into accountfactors such as body weight, gender, and in particular opioid toleranceand current treatment regime. The precise amount suitable in any casewill readily be determined by one of skill in the art.

In a further advantage of the present invention, the formulationsdescribed herein provide a very stable equilibrium level ofbuprenorphine once a small number of cycles of regular administrationhave been made. This stable level provides for excellent maintenancedosing and avoidance of withdrawal symptoms.

Furthermore, once a subject is stabilised by, for example, receipt ofweekly buprenorphine depot injections, that subject may then be movedonto bi-weekly (fortnightly) formulations and in due course monthlyformulations.

Furthermore, because the blood concentration of buprenorphine decayswith a half-life of 3-4 days, no sudden drop in plasma concentration isexperienced and this may help avoid or lessen withdrawal symptoms if thesubject elects to come off from opioid maintenance. Thus a treatmentregime may involve the transfer from daily to weekly to fortnightly tomonthly formulations. A transition may then be made to lower doses andin due course the very slow decay from a stable plateau may allowwithdrawal of opioid treatment with minimal withdrawal symptoms.

One key advantage of the various formulations of the present inventionis that they permit the inclusion of buprenorphine at surprisingly highloadings. This allows for decreased injection volumes, less pain oninjection and at the injection site and thus better patient compliance.Thus, the overall total buprenorphine content in the precursorformulations of the present invention will typically be 12% to 55% byweight of the total formulation. This may be chosen to be in a suitablerange for any particular application and may thus be, for example in theranges 15 to 25% or 30 to 50%. In one particularly preferred embodiment,higher buprenorphine loadings are used in combination with the use ofNMP as at least a part (e.g. at least 50% of component b)) of thesolvent component. Thus, precursor formulations comprising NMP may havea buprenorphine loading of greater than 30%, for example 31% to 55%, 32%to 55% or 35% to 50%.

In one embodiment, precursor formulations and all corresponding aspectsof the present invention include a polymer release matrix (as describedherein) and comprise buprenorphine at greater than 30% by weight (e.g.31 to 50% by weight). Such compositions will typically comprise NMP.

In an alternative embodiment, the precursor formulations and allcorresponding aspects of the present invention include a lipid releasematrix (as described herein) and comprise buprenorphine at greater than12% by weight (e.g. 12 to 50% by weight, preferably 25 to 50%, e.g. 31to 50% by weight). Such compositions will typically comprise NMP.

In a key embodiment, the pre-formulations of the present invention willgenerally be administered parenterally. This administration willgenerally not be an intra-vascular method but will preferably besubcutaneous, intracavitary or intramuscular. Typically theadministration will be by injection, which term is used herein toindicate any method in which the formulation is passed through the skin,such as by needle, catheter or needle-free injector.

Injection volumes for the precursor formulations of the presentinvention may be reduced because of the uniquely high level of activeagent incorporated. Injection volumes will preferably be no more than 5ml per administration, more preferably no more than 2 ml and mostpreferably no more than 1 ml. The prefilled devices of the inventionwill thus typically contain these volumes of composition. Prefilleddevices such as syringes containing ready-to-use precursor formulations(especially comprising lipid matrices but also possible with the polymerformulations of the present invention) of the present invention thusform a further aspect thereof.

One highly valuable aspect of the present invention relates to the useof lipid controlled release matrices in the formation of the precursorformulations and depot compositions of the invention. Such lipidmatrices are described herein and in documents cited herein.

The lipid-based pre-formulations of the present invention providenon-lamellar liquid crystalline depot compositions upon exposure toaqueous fluids, especially in vivo and in contact with body surfaces. Asused herein, the term “non-lamellar” is used to indicate a normal orreversed liquid crystalline phase (such as a cubic or hexagonal phase)or the L₃ phase or any combination thereof. The term liquid crystallineindicates all hexagonal, all cubic liquid crystalline phases and/or allmixtures thereof. Hexagonal as used herein indicates “normal” or“reversed” hexagonal (preferably reversed) and “cubic” indicates anycubic liquid crystalline phase unless specified otherwise. By use of thelipid pre-formulations of the present invention it is possible togenerate any phase structure present in the phase-diagram of componentsi) and ii) with water. This is because the pre-formulations can begenerated with a wider range of relative component concentrations thanprevious lipid depot systems without risking phase separation orresulting in highly viscous solutions for injection. In particular, thepresent invention provides for the use of phospholipid concentrationsabove 50% relative to the total amphiphile content. This allows accessto phases only seen at high phospholipid concentrations, particularlythe hexagonal liquid crystalline phases.

For many combinations of lipids, only certain non-lamellar phases exist,or exist in any stable state. It is a surprising feature of the presentinvention that compositions as described herein frequently exhibitnon-lamellar phases which are not present with many other combinationsof components. In one particularly advantageous embodiment, therefore,the present invention relates to compositions having a combination ofcomponents for which an I₂ and/or L₂ phase region exists when dilutedwith aqueous solvent. The presence or absence of such regions can betested easily for any particular combination by simple dilution of thecomposition with aqueous solvent and study of the resulting phasestructures by the methods described herein.

In a highly advantageous embodiment, the compositions of the inventionmay form an I₂ phase, or a mixed phase including I₂ phase upon contactwith water. The I₂ phase is a reversed cubic liquid crystalline phasehaving discontinuous aqueous regions. This phase is of particularadvantage in the controlled release of active agents and especially incombination with polar active agents, such as water soluble activesbecause the discontinuous polar domains prevent rapid diffusion of theactives. Depot precursors in the L₂ are highly effective in combinationwith an I₂ phase depot formation. This is because the L₂ phase is aso-called “reversed micellar” phase having a continuous hydrophobicregion surrounding discrete polar cores. L₂ thus has similar advantageswith hydrophilic actives.

In transient stages after contact with body fluid the composition cancomprise multiple phases since the formation of an initial surface phasewill retard the passage of solvent into the core of the depot,especially with substantial sized administrations of internal depots.Without being bound by theory, it is believed that this transientformation of a surface phase, especially a liquid crystalline surfacephase, serves to dramatically reduce the “burst/lag” profile of thepresent compositions by immediately restricting the rate of exchangebetween the composition and the surroundings. Transient phases mayinclude (generally in order from the outside towards the centre of thedepot): H_(II) or L_(α), I₂, L₂, and liquid (solution). It is highlypreferred that the composition of the invention is capable forming atleast two and more preferably at least three of these phasessimultaneously at transient stages after contact with water atphysiological temperatures. In particular, it is highly preferred thatone of the phases formed, at least transiently, is the I₂ phase.

It is important to appreciate that the preformulations of the presentinvention are of low viscosity. As a result, these preformulations mustnot be in any bulk liquid crystalline phase since all liquid crystallinephases have a viscosity significantly higher than could be administeredby syringe or spray dispenser. The preformulations of the presentinvention will thus be in a non-liquid crystalline state, such as asolution, L₂ or L₃ phase, particularly solution or L₂. The L₂ phase asused herein throughout is preferably a “swollen” L₂ phase containinggreater than 10 wt % of solvent (component b) having a viscosityreducing effect. This is in contrast to a “concentrated” or “unswollen”L₂ phase containing no solvent, or a lesser amount of solvent, orcontaining a solvent (or mixture) which does not provide the decrease inviscosity associated with the oxygen-containing, low viscosity solventsspecified herein.

Upon administration, the pre-formulations of the present inventionundergo a phase structure transition from a low viscosity mixture to ahigh viscosity (generally tissue adherent) depot composition. This takesthe form of generation of a non-lamellar phase from lipid-basedcontrolled release matrices or precipitation of a polymeric monolith inthe case of polymer solution precursor formulations. Generally, thiswill be a transition from a molecular (or polymer) solution, swollen L₂and/or L₃ phase to one or more (high viscosity) liquid crystallinephases or solid polymer. Such phases include normal or reversedhexagonal or cubic liquid crystalline phases or mixtures thereof. Asindicated above, further phase transitions may also take place followingadministration. Obviously, complete phase transition is not necessaryfor the functioning of the invention but at least a surface layer of theadministered mixture will form a liquid crystalline structure. Generallythis transition will be rapid for at least the surface region of theadministered formulation (that part in direct contact with air, bodysurfaces and/or body fluids). This will most preferably be over a fewseconds or minutes (e.g. up to 30 minutes, preferably up to 10 minutes,more preferably 5 minutes of less). The remainder of the composition maychange phase to a liquid crystalline phase more slowly by diffusionand/or as the surface region disperses.

In one preferred embodiment, the present invention thus provides apre-formulation as described herein of which at least a portion forms ahexagonal liquid crystalline phase upon contact with an aqueous fluid.The thus-formed hexagonal phase may gradually disperse, releasing theactive agent, or may subsequently convert to a cubic liquid crystallinephase, which in turn then gradually disperses. It is believed that thehexagonal phase will provide a more rapid release of active agent, inparticular of hydrophilic active agent, than the cubic phase structure,especially the I₂ and L₂ phase. Thus, where the hexagonal phase formsprior to the cubic phase, this will result in an initial release ofactive agent to bring the concentration up to an effective levelrapidly, followed by the gradual release of a “maintenance dose” as thecubic phase degrades. In this way, the release profile may becontrolled.

Without being bound by theory, it is believed that upon exposure (e.g.to body fluids), the pre-formulations of the invention lose some or allof the organic solvent included therein (e.g. by diffusion and/orevaporation) and in some cases take in aqueous fluid from the bodilyenvironment (e.g. moist air close to the body or the in vivoenvironment) such that at least a part of the lipid formulationsgenerate a non-lamellar, particularly liquid crystalline phasestructure. Polymeric precursor solutions lose solvent to the biologicalenvironment and precipitate a solid polymer. In most cases thesenon-lamellar structures are highly viscous and are not easily dissolvedor dispersed into the in vivo environment and are bioadhesive and thusnot easily rinsed or washed away. Furthermore, because the non-lamellarstructure has large polar, apolar and boundary regions, it is highlyeffective in solubilising and stabilising many types of active agentsand protecting these from degradation mechanisms. As the depotcomposition formed from the pre-formulation gradually degrades over aperiod of days, weeks or months, the active agent is gradually releasedand/or diffuses out from the composition. Since the environment withinthe depot composition is relatively protected, the pre-formulations ofthe invention are highly suitable for active agents with a relativelylow biological half-life (see above).

It is an unexpected finding of the present inventors that thepre-formulations result in a depot composition that have very little“burst” effect in the active agent release profile. This is unexpectedbecause it might be expected that the low viscosity mixture (especiallyif this is a solution) of the pre-composition would rapidly lose activeagent upon exposure to water. In fact, very high performance is providedin comparison with existing formulations, as is seen from FIGS. 4a and4b below. In one embodiment, the invention thus provides injectablepreformulations and resulting depot compositions wherein the highestplasma concentration of active after administration is no more than 5times the average concentration between 24 hours and 5 days ofadministration. This ratio is preferably no more than 4 times and mostpreferably no more than 3 times the average concentration.

It is a considerable advantage of both the lipid-containing precursorformulations and the polymer-matrix precursor formulations of thepresent invention that they may be provided in storage-stable,ready-to-administer form. That is to say, the precursor formulations ofthe present invention may be provided in a form that requires no furthercombining of components in order to generate a formulation that issuitable for injection. Thus the invention correspondingly provides anadministration device containing at least one precursor formulation asdescribed herein wherein the formulation is ready for administrationand/or administrable without any further combination or mixing ofcomponents. This contrasts with many controlled-release products,particularly polymeric controlled-release formulations, which requirevarious components to be combined before delivery to the patient. Suchan administration device will typically contain a dose suitable for asingle administration where the administration may be once-weekly,once-fortnightly, once-monthly or once every two or three months. In allcases, the dose of buprenorphine will be selected so as to provide overthe whole of the dosing period (at steady state) a Cmax and Cmin thatare within the Cmax to Cmin range experienced following daily sublingualbuprenorphine administration. Suitable administration devices includeprefilled syringes with optional needle stick prevention safety deviceand/or auto-injector, pen cartridge systems and similar devices.

Suitable administration devices of the invention include a ready-to-usebuprenorphine formulation of the present invention in a cartridge pencombination or prefilled syringe device, optionally equipped with aneedle stick protecting safety device or auto-injector. The device mayhave a needle with a gauge higher than 18 G, preferably above 20 G, morepreferably above 22 G (for example 23 G or 25 G). The buprenorphineformulation will generally be a precursor formulation as describedherein in any embodiment. Such a formulation will generally have aviscosity in the range of 100-500 mPas.

For ease of self-administration, the device of the present invention maybe or may be used with or incorporated into an auto-injection device orpen-cartridge device. Such a device may be disposable or reusable.

By “storage stable” as used herein is indicated that a compositionmaintains at least 90% of the original active agent content afterstorage for 36 months at 25° C. and 60% relative humidity. This ispreferably at least 95% and more preferably at least 98%.

A ready-to-administer product has obvious advantages for ease ofadministration and in particular, if a opioid dependence product or longterm pain relief medication is to be administered by a healthcareprofessional at regular intervals to a population of patients, asignificant amount of time may be required in preparation of thematerials prior to injection. In contrast, if the product is ready touse or even provided in a pre-filled administration device then thehealthcare professional may spend their time in consultation withpatients rather than in mixing medications.

The methods of treatment and/or prophylaxis, and corresponding uses inmanufacture, of the present invention will be for any medical indicationfor which opioids are indicated. In particular, chronic conditions suchas chronic pain (e.g. in arthritis, after surgery, in palliative cancertreatment etc.) are particularly suitable for the use of the presentdepot formulations and their precursors. The most suitable indicationswill, however, include pain, diarrhoea, depression, opioid dependence,opioid addiction, and the symptoms of opioid withdrawal. Of these, thepresent compositions are most preferably used in methods for thetreatment and/or prophylaxis of opioid dependence, opioid addiction,and/or the symptoms of opioid withdrawal. Opioid maintenance therapy(opioid substitution therapy) is the most preferred treatment method foruse of the formulations of the invention.

Cases where opioid dependence and/or opioid addiction have resulted fromopioid abuse are particularly suitable for treatment with the presentcompositions because they offer advantages in terms of patientcompliance, where the patient's lifestyle may not be compatible withregular attendance at a clinic or other site of medical treatment.

In one aspect, the present invention therefore provides for a method ofdetoxification treatment of a (preferably human) mammalian subject wherethe subject has or has had an opioid dependence, addiction, or habit,and/or where the subject is suffering from or is at risk of sufferingfrom withdrawal symptoms from opioid administration. Such adetoxification method will comprise at least one administration of aprecursor formulation of the present invention. Such a formulation maybe any such formulation as described herein and as evident from thatdisclosure.

In a further aspect, the present invention therefore provides for amethod of maintenance treatment of a (preferably human) mammaliansubject where the subject has or has had an opioid dependence,addiction, or habit, and/or where the subject is suffering from or is atrisk of suffering from withdrawal symptoms from opioid administration.Such a maintenance treatment method will comprise at least one and morecommonly multiple administrations of a precursor formulation of thepresent invention. Such a formulation may be any such formulation asdescribed herein and as evident from that disclosure. Suchadministrations may be, for example, once weekly, once every two weeks(fortnightly) or once monthly.

In a similar aspect, the present invention provides a method for opioidmaintenance therapy comprising at least six administrations (e.g. 6-120administrations) of precursor formulations of the present invention atperiods of 28±7 days between each administration.

It is notable that the low ratio of Cmax to Cmin over 28 days providedby the products of the present invention demonstrate that a highlyeffective once-monthly formulation can be generated according to thepresent invention. It is preferable that the ratio of Cmax to Cmin over28 days be no more than 200, preferably no more than 50, or no more than10. preferably no more than 5, more preferably no more than 3 and mostpreferably no more than 2.8, measured as plasma buprenorphineconcentrations.

In one key aspect, the precursor formulations of the invention are givenas a subcutaneous injection. Compared with the sublingual buprenorphineproducts on the market, the products of the invention have one or moreof the following advantages: 1) Rapid therapeutic onset (with maximumplasma concentrations established within 24 hours after injection)followed by steady long-acting release, 2) Reduced variation inbuprenorphine plasma levels over time (stable plasma levels attained forat least 7 days) resulting in more therapeutic levels and a possiblereduction in morning “cravings”, 3) Less frequent dosing resulting inreduced frequency of clinic visits and need for medical support, 4)Significantly higher bioavailability and efficacy-over-dose ratio,meaning less drug substance in circulation and on the street, 5)Decreased risk of drug diversion, 6) Easier dose adjustment, 7)“Ready-to-use” dosage formulation, 8) high buprenorphine loading, 9)good systemic tolerability and 10) good local tolerability at theadministration site.

The Invention will now be further illustrated by reference to thefollowing non-limiting Examples and the attached Figures, in which;

FIG. 1 shows the cumulative release of methylene blue (MB) from a depotformulation comprising PC/GDO/EtOH (45/45/10 wt %) when injected intoexcess water;

FIG. 2 demonstrates the non-linear decrease of pre-formulation viscosityupon addition of N-methyl pyrolidone (NMP) and ethanol (EtOH). FIG. 2illustrates a decrease in viscosity at 25° C. of the depot precursor onaddition of solvents. PC/GDO (50/50 wt/wt) is a precursor to a reversedhexagonal H_(II) phase and PC/GDO (40/60 wt/wt) is a precursor to areversed cubic I₂ phase;

FIG. 3 shows stability of buprenorphine at long-term 25° C./60% RH andaccelerated 40° C./75% RH conditions in Formulation A1 (also referred toas CAM2038) as described in Example 16;

FIG. 4 shows plasma profiles in rats (N=6) after subcutaneous injectionof Formulation A18 and A3 (Example 11) at doses of 140 mg/kg and 50mg/kg, respectively;

FIG. 5 shows X-ray diffractograms of the BJ formulations in PBScontaining different amounts of BUP. Samples are prepared at formulationto PBS weight ratio of 1/9. Upon increasing BUP concentration the Fd3mliquid crystalline structure remains unchanged;

FIG. 6 shows X-ray diffractograms of the BJ formulation containing 35 wt% of BUP as a function of temperature. Sample is prepared at formulationto PBS weight ratio of 1/9. Upon increasing temperature from 25 to 42°C. the Fd3m liquid crystalline structure remains unchanged;

FIG. 7 shows plasma concentration of BUP following administration oflipid (solid point markers) and PLGA (open point markers) depotprecursor formulations of the present invention at variousconcentrations;

FIG. 8 shows a comparison of Buprenorphine release inready-to-administer polymeric compositions of Example 17 (closedmarkers) with previous compositions of PCT/GB2011/051057 (open markers);

FIG. 9 shows a comparison of Buprenorphine release inready-to-administer lipid compositions of Example 17 (solid markers)with previous compositions of PCT/GB2011/051057 (open markers);

FIG. 10—Blood plasma concentration at which rescue buprenorphine wasrequested following depot administration plotted against the subject'sprevious daily maintenance dose prior to transfer to depotadministration.

EXAMPLES Example 1

Availability of Various Liquid Crystalline Phases in the Depot by Choiceof Composition

Injectable formulations containing different proportions of phosphatidylcholine (“PC”—Epikuron 200) and glycerol dioleate (GDO) and with EtOH assolvent were prepared to illustrate that various liquid crystallinephases can be accessed after equilibrating the depot precursorformulation with excess water.

Appropriate amounts of PC and EtOH were weighed in glass vials and themixture was placed on a shaker until the PC completely dissolved to forma clear liquid solution. GDO was then added to form an injectablehomogenous solution.

Each formulation was injected in a vial and equilibrated with excesswater. The phase behaviour was evaluated visually and between crossedpolarizes at 25° C. Results are presented in Table 1.

TABLE 1 Phase behaviour of PC/GDO formulations. Formulation PC (wt %)GDO (wt %) EtOH (wt %) Phase in H₂O A 22.5 67.5 10.0 L₂ B 28.8 61.2 10.0I₂ C 45.0 45.0 10.0 H_(II) D 63.0 27.0 10.0 H_(II)/L_(α) L₂ = reversedmicellar phase I₂ = reversed cubic liquid crystalline phase H_(II) =reversed hexagonal liquid crystalline phase L_(α) = lamellar phase

Example 2

In Vitro Release of a Water-Soluble Substance

A water-soluble colorant, methylene blue (MB) was dispersed informulation C (see Example 1) to a concentration of 11 mg/g formulation.When 0.5 g of the formulation was injected in 100 ml water a stiffreversed hexagonal H_(II) phase was formed. The absorbency of MBreleased to the aqueous phase was followed at 664 nm over a period of 10days. The release study was performed in an Erlenmeyer flask at 37° C.and with low magnetic stirring.

The release profile of MB (see FIG. 1) from the hexagonal phaseindicates that this (and similar) formulations are promising depotsystems. Furthermore, the formulation seems to give a low initial burst,and the release profile indicates that the substance can be released forseveral weeks; only about 50% of MB is released after 10 days.

Example 3

Viscosity in PC/GDO (5:5) or PC/GDO (4:6) on Addition of Solvent (EtOH,PG and NMP)

A mixture of PC/GDO/EtOH with approximately 25% EtOH was manufacturedaccording to the method in Example 1. All, or nearly all, of the EtOHwas removed from the mixture with a rotary evaporator (vacuum, 40° C.for 1 h followed by 50° C. for 2 h) and the resulting mixture wasweighed in glass vial after which 1, 3, 5, 10 or 20% of a solvent (EtOH,propylene glycol (PG) or n-methyl pyrrolidone (NMP)) was added. Thesamples were allowed to equilibrate several days before the viscositywas measured with a CarriMed CSL 100 rheometer equipped with automaticgap setting.

This example clearly illustrates the need for solvent with certain depotprecursors in order to obtain an injectable formulation (see FIG. 2).The viscosity of solvent-free PC/GDO mixtures increases with increasingratio of PC. Systems with low PC/GDO ratio (more GDO) are injectablewith a lower concentration of solvent.

Example 4

Preparation of Depot Precursor Compositions with Various Solvents.

Depending on composition of the formulation and the nature andconcentration of active substance certain solvents may be preferable.

Depot precursor formulations (PC/GDO/solvent (36/54/10)) were preparedby with various solvents; NMP, PG, PEG400, glycerol/EtOH (90/10) by themethod of Example 1. All depot precursor compositions were homogeneousone phase solutions with a viscosity that enabled injection through asyringe (23G—i.e. 23 gauge needle; 0.6 mm×30 mm). After injectingformulation precursors into excess water a liquid crystalline phase inthe form of a high viscous monolith rapidly formed with NMP and PGcontaining precursors. The liquid crystalline phase had a reversed cubicmicellar (I₂) structure. With PEG400, glycerol/EtOH (90/10) theviscosification/solidification process was much slower and initially theliquid precursor transformed to a soft somewhat sticky piece. Thedifference in appearance probably reflects the slower dissolution ofPEG400 and glycerol towards the excess aqueous phase as compared to thatof EtOH, NMP and PG.

Example 5

Robustness of the Behaviour of the Formulation Against Variations in theExcipient Quality.

Depot precursor formulations were prepared with several different GDOqualities (supplied by Danisco, Denmark), Table 2, using the method ofExample 1. The final depot precursors contained 36% wt PC, 54% wt GDO,and 10% wt EtOH. The appearance of the depot precursors was insensitiveto variation in the quality used, and after contact with excess water amonolith was formed with a reversed micellar cubic phase behaviour (I₂structure).

TABLE 2 Tested qualities of GDO. GDO Monoglyceride DiglycerideTriglyceride quality (% wt) (% wt) (% wt) A 10.9 87.5 1.6 B 4.8 93.6 1.6C 1.0 97.3 1.7 D 10.1 80.8 10.1 E 2.9 88.9 8.2 F 0.9 89.0 10.1

Example 6

Degradation of Depot Formulation in the Rat.

Various volumes (1, 2, 6 ml/kg) of the depot precursor (36% wt PC, 54%wt GDO, and 10% wt EtOH) were injected in the rat and were removed againafter a period of 14 days. It was found that substantial amounts of theformulations were still present subcutaneously in the rat after thistime, see Table 3.

TABLE 3 Mean diameter of depot monolith. Mean diameter Mean diameterDose (ml/kg) day 3 (mm) day 14 (mm) 1 (n = 3) 15.8 12.5 2 (n = 3) 18.515.3 6 (n = 3) 23.3 19.3

Example 7

Compositions Containing PC and Tocopherol.

Depot precursor formulations were prepared with several differentPC/α-tocopherol compositions using the method of Example 1 (PC was firstdissolved in the appropriate amount of EtOH and thereafter α-tocopherolwas added to give clear homogenous solutions).

Each formulation was injected in a vial and equilibrated with excesswater. The phase behaviour was evaluated visually and between crossedpolarizes at 25° C. Results are presented in Table 4.

TABLE 4 Phase behaviour of PC/α-tocopherol formulations. α-tocopherol PCEthanol Phase in excess H₂O 2.25 g 2.25 g 0.5 g H_(II) 2.7 g 1.8 g 0.5 gH_(II)/I₂ 3.15 g 1.35 g 0.5 g I₂ 3.6 g 0.9 g 0.5 g I₂/L₂

Example 8

In Vitro Release of Water-Soluble Disodium Fluorescein.

A water-soluble colorant, disodium fluorescein (Fluo), was dissolved ina formulation containing PC/α-tocopherol/Ethanol (27/63/10 wt %) to aconcentration of 5 mg Fluo/g formulation. When 0.1 g of the formulationwas injected in 2 ml of phosphate buffered saline (PBS) a reversedmicellar (I₂) phase was formed. The absorbency of Fluo released to theaqueous phase was followed at 490 nm over a period of 3 days. Therelease study was performed in a 3 mL vial capped with an aluminiumfully tear off cap at 37° C. The vial was placed on a shaking table at150 rpm.

The release of Fluo from the PC/α-tocopherol formulation (see Table 5)indicates that this (and similar) formulations are promising depotsystems. Furthermore, the absence of a burst effect is noteworthy, andthe release indicates that the substance can be released for severalweeks to months; only about 0.4% of Fluo is released after 3 days.

TABLE 5 In vitro release of disodium fluorescein from PC/α-tocopherolcomposition. % release (37° C.) Formulation 24 h 72 hPC/α-tocopherol/EtOH: 27/63/10 wt % <0.1* 0.43 *Release below detectionlimit of the absorbance assay

Example 9

Solubility of Buprenorphine in Depot Precursor Formulations.

Buprenorpine solubility in formulation precursors was determined by thefollowing protocol; buprenorphine in excess was added to formulationprecursors and samples were equilibrated by end-over-end mixing atambient room temperature for four days. Excess buprenorphine was removedby filtration and the concentration in precursor formulations wasdetermined with HPLC. Formulation precursors in the table below differby the additional solvent (ethanol (EtOH), benzyl alcohol (BzOH),polyethyleneglycol 400 (PEG400), benzyl benzoate (BzB), anddimethylsulphoxide (DMSO)).

TABLE 6 Buprenorphine solubility in various precursor formulations.Composition of formulation precursor Additional Buprenorphine SPC/ GDO/EtOH/ solvent/ solubility/ Sample wt % wt % wt % wt % wt % 1 47.5 47.5 5— 10.4 2 45 45 5 EtOH/5 10.3 3 45 45 5 BzOH/5 9.9 4 45 45 5 PEG400/510.8 5 45 45 5 BzB/5 11.2 6 45 45 5 DMSO/5 15.2

Example 10

In Vitro Behaviour of Buprenorphine Depot Precursor Formulations.

After injection into excess water or excess saline (0.9% NaCl) a liquidcrystalline phase in the form of a high viscous monolith formed with allformulation precursors described in Example 14. In general thetransformation was somewhat slower with additional solvent, whilebuprenorphine appeared not to have a strong influence on the monolithformation.

Example 11

Ready-to-Administer Lipid Formulations

The formulations indicated in Table 7 below comprising buprenorphine,lipids and solvent were generated by adding the respective component inthe required proportions to sterile injection glass vials followed bycapping with sterile rubber stoppers and aluminium crimp caps. Mixing ofthe formulations (sample sizes 5-10 g) was performed by placing thevials on a roller mixer at ambient room temperature until liquid andhomogenous formulations were obtained. The formulations were finallysterile filtered through 0.22 μm PVDF membrane filters using ca 2.5 barnitrogen pressure.

The lipids used were Lipoid 5100 (SPC) from Lipoid, Germany, and RyloDG19 Pharma (GDO) from Danisco, Denmark.

TABLE 7 Ready-to-administer lipid buprenorphine compositions (wt %).Formulation name BUP SPC GDO EtOH NMP A1 5.29 42.36 42.36 10.00 — A27.93 41.04 41.04 10.00 — A3 5.29 44.10 44.10 6.50 — A4 7.81 43.60 43.605.00 — A5 7.93 49.25 32.83 10.00 — A6 7.93 32.83 49.25 10.00 — A7 7.9338.54 38.54 15.00 — A8 7.93 36.04 36.04 20.00 — A9 5.29 33.88 50.8310.00 — A10 5.29 46.59 38.12 10.00 — A11 5.29 50.83 33.88 10.00 — A120.53 44.74 44.74 10.00 — A13 1.06 44.47 44.47 10.00 — A14 2.11 43.9443.94 10.00 — A15 15.0 37.5 37.5 — 10.0 A16 15.0 32.5 32.5 — 20.0 A1735.0 17.5 17.5 — 30.0 A18 35.0 14.0 21.0 — 30.0 A19 15.0 35.0 35.0 —15.0 A20 15.0 30.0 30.0 — 25.0 A21 30.0 25.0 25.0 — 20.0 A22 40.0 12.018.0 — 30.0 A23 30.0 16.0 24.0 — 30.0 A24 25.0 22.0 33.0 — 30.0 A25 15.032.5 32.5 5.0 15.0

Example 12

Ready-to-Administer Polymer Formulations

The formulations indicated in Table 8 below comprising buprenorphine,polymer and solvent were generated by adding the respective component inthe required proportions to a sterile injection glass vial followed bycapping with sterile rubber stopper and aluminium crimp cap. Mixing ofthe formulations (sample sizes 5-10 g) was performed by placing thevials on a roller mixer at ambient room temperature until liquid andhomogenous formulations were obtained. The formulations were finallysterile filtered through 0.22 μm PVDF membrane filters using ca 2.5 barnitrogen pressure.

The polymer used was PLGA (polymer type 50/50Poly(DL-lactide-co-glycolide) with inherent viscosity 0.59 dL/g) fromBirmingham Polymers Inc., USA.

TABLE 8 Ready-to-administer polymer buprenorphine compositions (wt %).Formulation name BUP PLGA NMP B1 15.0 21.25 63.75 B2 20.0 20.00 60.00 B325.0 18.75 56.25 B4 32.5 16.9 50.6 B5 35.0 16.2 48.8 B6 40.0 15.0 45.0

Example 13

Formulations Comprising Water and Buprenorphine Salts

The formulations indicated in Table 9 below comprising buprenorphine,lipids and solvent were generated as described in Example 16 above. Forthe formulations comprising water, the additives hydrochloric acid (HCl)and citric acid (CA) were first dissolved in the aqueous phase followedby addition to the other components. The respective buprenorphine saltforms (i.e., hydrochloride, citrate, benzoate and pamoate salts) aregenerated in the formulations after mixing of all components.

The lipids used were Lipoid 5100 (SPC) from Lipoid, Germany, and RyloDG19 Pharma (GDO) from Danisco, Denmark. Benzoic acid and pamoic (orembonic) acid are abbreviated Bz and PAM, respectively.

TABLE 9 Ready-to-administer lipid buprenorphine compositions comprisingwater and buprenorphine salts (wt %). Formulation HCl(aq) name BUP SPCGDO EtOH NMP pH 0.52 WFI CA Bz PAM C1 2.11 33.95 33.95 15.00 — 15.00 — —— — C2 5.29 31.86 31.86 15.00 — — 15.00 1.00 — — C3 1.06 33.97 33.9715.00 — — 15.00 1.00 — — C4 2.11 32.95 32.95 15.00 — — 15.00 2.00 — — C52.11 33.75 33.75 15.00 — — 15.00 0.40 — — C6 2.11 38.75 38.75 10.00 — —10.00 0.40 — — C7 5.29 41.10 41.10 10.00 — — — — 2.60 — C8 5.29 35.1635.16 5.00 15.00 — — — — 4.39 C9 5.29 35.71 35.71 5.00 15.00 — — — —3.29 C10 5.29 36.26 36.26 5.00 15.00 — — — — 2.19 C11 1.06 34.47 34.4715.00 — — 15.00 — — — C12 2.11 33.95 33.95 15.00 — — 15.00 — — — C131.06 39.47 39.47 10.00 — — 10.00 — — —

Example 14

Lipid Buprenorphine Formulation Filled into Pre-Filled Syringes.

Formulation A1, hereinafter referred to as CAM2038, was manufacturedaccording to Example 11 above at a batch size of 100 mL. The formulationwas filled into 1 mL (long) pre-filled syringes (1.0 mL longGerresheimer glass, staked needle 25G 16 mm thin wall, oily siliconized,batch no: 1000102210) and plunger stoppers (West 2340 4432/50/GRAU B240Westar® RS, lot. Nr: 1112020528) and plunger rods (Gerresheimer Plungerrod 1 mL long 55103, art no: 551030001) were assembled.

Example 15

Controlling PK Profile by Composition

Formulations A3 and A18 (see Example 11) were administeredsubcutaneously to rats in doses of 50 and 140 mg/kg, respectively (N=6per group). Blood samples were collected up to 21 days after dosing. Theplasma concentrations were determined as described below and therespective pharmacokinetic profiles are shown in FIG. 4. As can be seen,whereas Formulation A3 provides a short time to Cmax (about 24 hrs) andthereafter stable and slowly declining plasma levels, Formulation A18provides a longer time to Cmax (ca 8 days) and thereafter slowlydeclining plasma levels. It is also noteworthy that despite the highbuprenorphine load of 35 wt % in Formulation A18 and the higher doseadministered, the plasma levels over the first days are lower comparedto Formulation A3.

Protocol:

The formulation A3/A18 was administered subcutaneously to rats in dosesof 50 and 140 mg/kg respectively and blood samples were collectedpre-dose, 1 hrs, 6 hrs, 1 day, 2 days, 5 days, 8 days and 14 days afterdosing. In a separate group, Temgesic (aqueous injection solution ofbuprenorphine hydrochloride with an equivalent buprenorphine baseconcentration of 0.30 mg/mL) was administered intravenously (0.45 mg/kg,N=6) and blood samples were collected pre-dose, 1 min, 5 min, 10 min, 30min, 60 min, 3 hrs, 6 hrs and 24 hrs. The plasma concentrations weredetermined with the aid of a commercial ELISA kit adapted for analysisof buprenorphine in rat plasma. The area-under-the-curve (AUC) for therespective treatment groups was calculated and the absolutebioavailability was calculated by comparing the AUC for the subcutaneousFormulation A3 dose groups with the AUC for the Temgesic intravenousdose group. The results revealed very high absolute bioavailability forall Formulations.

Example 16

The lipid liquid crystalline phase structure of hydrated formulationscontaining high concentration buprenorphrine was studied by synchrotronSAXD. Diffractograms were recorded at the I9-11-4 SAXS beamline(MAX-lab, Lund University). Herein, synchrotron SAXS is used to studythe effect of BUP concentration on the liquid crystalline (LC) phasestructure for 40/60 SPC/GDO and 70/30 (Lipid+BUP)/NMP (“BJ”).Temperature effect on the LC phase structure containing 35 wt % of BUPwas also studied at 25, 37 and 42° C. to cover the relevant temperaturerange.

Material

TABLE 10 Excipients used in the experiment. Explanation AbbreviationDelivered by Soy phosphatidylcholine SPC Lipoid Glycerol dioleate (RyloDG 19) GDO Danisco N-Methyl-2-pyrrolidone NMP ISP Phosphate bufferedsaline PBS Sigma-Aldrich Sterile water H2O Apoteket

Briefly, the lipid formulations were prepared by weighing all componentsfollowed by mixing on a roller table at room temperature. Formulationswere then equilibrated in phosphate buffered saline (PBS) at weightratio 1/9 at room temperature for 5 days and their transparency andhomogeneity were noted 3 and 4 days after hydration, respectively.Approximately 100 mg of each formulation was equilibrated with PBSbuffer.

Synchrotron SAXD measurements were performed at the I9-11-4 beamline,MAX-lab. The samples were exposed to X-rays for 60 s at each of thethree temperatures (25, 37 and 42° C.). The samples were allowed toequilibrate for at least 5 minutes at each temperature before thediffratograms were recorded.

Table 11 lists the composition of samples studied by SAXD. The SAXD datais shown and further discussed below.

TABLE 11 “BJ”-BUP formulations with different fraction of BUP and PBSdilution. Formulation ID No: SPC/GDO Lipid/NMP/BUP Formulation/PBS 421740/60 69.7/30.3/0   1/9 4216 40/60 59.9/29.8/10.3 1/9 4215 40/6049.8/30.2/20.0 1/9 4214 40/60 39.9/30.2/29.9 1/9 4213-5 40/6034.9/30.1/35.0 1/9

Effect of BUP in Formulations

The “BJ” (high loading, 35% BUP) formulations with a 40/60 SPC/GDO and30% NMP exhibit a cubic micellar (I2) phase (Fd3m) at all fractions ofBUP (0-35%), as seen in FIG. 5. The cubic Fd3m structure is alsopreserved when heating from 25 to 37 and 42° C. (FIG. 6).

Conclusion

The lipid liquid crystalline phases of hydrated formulation containingBUP has been studied with synchrotron SAXS. The studies show that evenup to at least 35% BUP loading, the characteristics of the desiredliquid crystalline lipid phases are shown when preformulations are addedto aqueous buffer (10% formulation in buffer). This phase behaviour isshown at 25° C., 37° C. and 42° C. and 35% BUP.

Example—17 High Loading PLGA and Lipid Precursor Formulations

Formulations 2038BUP-BJ (lipid—352 mg/mL BUP) and 2038UP-AL (PLGA—150mg/mL BUP) were prepared according to the protocol of the previousExamples (16 and 12) and with the components as shown below (in wt %).Each composition was tested by subcutaneous injection into 6 rats ateach of several dosage levels.

PK-12-454 Test item BUP SPC GDO NMP 2038BUP-BJ 35.00 14.00 21.00 30.00Route of Dose Dose of Group No of adminis- volume BUP No animalsTreatment tration (mL/kg) (mg/kg) 1 6 2038BUP-BJ s.c. 0.17 60 2 62038BUP-BJ s.c. 0.29 100 3 6 2038BUP-BJ s.c. 0.40 140 4 6 2038BUP-BJs.c. 0.51 180

PK-11-415 Test item BUP PLGA NMP 2038BUP-AL 15.00 21.25 63.75 Route ofDose of Dose Group No of adminis- BUP volume No animals Treatmenttration (mg/kg) (mL/kg) 1 6 2038BUP-AL s.c. 30 0.2 2 6 2038BUP-AL s.c.60 0.4 3 6 2038BUP-AL s.c. 90 0.6

FIG. 7 shows the results of plasma BUP measurements for several weeksfollowing administration of the two compositions. It is notable that:

-   -   The lipid formulation shows a gently tapering profile over the        study period    -   The lipid formulation shows a plasma level at the 28-day        re-administration point which depends directly and approximately        proportionally upon the administered dose.    -   The PLGA formulation shows a flatter profile with lower total        AUC during the study period.    -   The PLGA formulation is apparently less dose proportional, with        the 30 mg and 60 mg doses providing the same plasma profile for        the first month.

For comparison, the precursor formulations of the present invention wereplotted against the data provided in PCT/GB2011/051057 relating to thefollowing compositions:

TA 1: 15% Buprenorphine base in 45% 50/50 PLGH (26 kD) and 55% NMP

TA 2: 20% Buprenorphine base in 40% 50/50 PLGH (17 kD) and 60% NMP

TA 3: 20% Bup base in 20% 50/50 PLGH (26 Kd), 20% 50/50 PLGH (12 kD) and60% NMP

TA 4: 20% Buprenorphine base in 45% 50/50 PLGH (12 kD) and 55% NMP

FIG. 8 shows the comparison of the ready-to-administer compositions ofthe present invention with the previously known polymer depotcomposition of PCT/GB2011/051057. It is evident that even at much lowerdoses the amount of available BUP in the compositions of the presentinvention is greatly increased. A typical rat weighs around 330 g andthus a 60 mg/kg does equates to around 20 mg/rat but provides similarAUC availability to 100 mg/rat for the known formulation.

FIG. 9 shows the comparison of the ready-to-administer compositions ofthe present invention with the previously known polymer depotcomposition of PCT/GB2011/051057. It is evident that the AUCbioavailability, release shape and dose proportionality are allsignificantly better for the lipid compositions of the presentinvention. In particular, the lowest dose of 60 mg/kg equates to around20 mg/rat but provides much better release profile and bioavailabilitythan the known composition at 100 mg/rat.

The invention claimed is:
 1. A method of administering an opioidmaintenance treatment to a patient, the method comprising administeringa composition to the patient from a pre-filled syringe containing thecomposition, wherein the composition is administered subcutaneously tothe patient once-weekly and comprises about 5% by weight ofbuprenorphine; about 10% by weight of ethanol; about 42% by weight of aphosphatidylcholine; and about 42% by weight of glycerol dioleate. 2.The method of claim 1, wherein the patient suffers from an opioiddependency.
 3. The method of claim 2, wherein the patient suffers fromopioid withdrawal.
 4. The method of claim 1, wherein administering theopioid maintenance treatment treats pain in the patient.
 5. The methodof claim 1, wherein the composition comprises 3 to 40 mg ofbuprenorphine.
 6. The method of claim 1, wherein the patient isreceiving or has previously received an oral dosage form comprisingbuprenorphine.
 7. The method of claim 6, wherein the oral dosage form issublingual.
 8. The method of claim 1, wherein the composition, aftercontact with an aqueous fluid, forms a liquid crystalline phasestructure.
 9. The method of claim 8, wherein the liquid crystallinephase structure is a non-lamellar crystalline phase structure.
 10. Themethod of claim 1, wherein, at steady state plasma concentrations, theCmin and Cmax of buprenorphine in the patient is between about 0.4 ng/mLand 10 ng/mL.
 11. The method of claim 1, wherein the Cmin and Cmax ofbuprenorphine in the patient is between about 0.4 ng/mL and 10 ng/mL forat least a week after administration.
 12. The method of claim 1, whereinthe blood plasma concentration of buprenorphine in the patient is atleast 0.2 ng/mL for at least a week.
 13. A method of administering anopioid maintenance treatment to a patient, the method comprisingadministering a composition to the patient from a pre-filled syringecontaining the composition, wherein the composition is administeredsubcutaneously to the patient once-weekly and comprises about 5.29% byweight of buprenorphine; about 10% by weight of ethanol; about 42.36% byweight of a phosphatidylcholine; and about 42.36% by weight of glyceroldioleate.
 14. The method of claim 13, wherein the patient suffers froman opioid dependency.
 15. The method of claim 14, wherein the patientsuffers from opioid withdrawal.
 16. The method of claim 13, wherein thecomposition comprises 3 to 40 mg of buprenorphine.